Pemphigus is a group of potentially life-threatening antibody-mediated autoimmune diseases of the skin and other stratified epithelia in which acantholysis ? the loss of cell adhesion ? causes skin blistering and erosions. Acantholysis in pemphigus is caused by autoantibodies directed against desmosome cell-adhesive junctions ? specifically against the transmembrane cadherin- family proteins that bind between cells to mediate adhesion in desmosomes. Several subtypes of pemphigus disease are known, including two major forms pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Broadly, PV is characterized by acantholysis in the basal layers of mucosae (mucosal form) or mucosae and skin (muco-cutaneous form), while PF is characterized by acantholysis specifically in the subcorneal upper layers of the skin. Pathogenic pemphigus autoantibodies have been identified from patients with each form of the disease, but structural information on pemphigus autoantibodies is lacking. Thus, the precise epitopes targeted by pemphigus autoantibodies, and the antibody regions (paratopes) that mediate recognition, remain unknown. The overall goal of the research proposed here is to bring atomic-level definition to the study of pemphigus disease through the application of modern methods of structural biology. Atomic resolution co-crystal structures will unambiguously identify functional regions and define the precise molecular interactions mediating recognition between pemphigus autoantibodies and the cadherin cell-adhesion proteins they target. In addition, to determine how different pemphigus autoantibodies impair desmosome structure and cause blistering, we will analyze their effects on reconstituted desmosome junctions at high resolution using cryo-EM tomography. The research proposed here will produce an atomic-level understanding of the interaction of pemphigus autoantibodies with desmosomes, and is expected to transform our understanding of pemphigus disease.